The hydrophilic polymer poly(ethylene glycol), abbreviated “PEG”, is of considerable utility in biological applications and in medicine. PEG is a polymer that is soluble in water and in many organic solvents, is non-toxic, and non-immunogenic. In recent years, the use of PEG has expanded into the biomedical, biotechnical and pharmaceutical arenas to encompass a variety of applications. For instance, covalent attachment of PEG to therapeutic polypeptides has been employed to shield antigenic epitopes of the polypeptide to reduce reticuloendothelial clearance and proteolytic degradation of the polypeptide. PEG conjugation to therapeutically active polypeptides or small molecules can also be used to increase the circulating half-life, improve solubility, reduce renal filtration, or alter the biodistribution of a bioactive agent.
Another use of PEG is to form a crosslinked matrix or gel of PEG molecules which is substantially non-soluble, but swellable in water. PEG hydrogels, which are water-swollen gels, have been used for both wound covering and drug delivery. PEG hydrogels are typically prepared by incorporating the soluble, hydrophilic polymer into a chemically crosslinked network or matrix so that addition of water produces an insoluble, swollen gel. One application of such hydrogels involves the delivery of drugs. In one approach, a therapeutic agent for delivery from a hydrogel is not covalently attached to the PEGs forming the hydrogel, but rather is entrapped within the crosslinked hydrogel matrix and passes through interstices in the matrix upon release.
Many of the commonly employed methods for preparing hydrogels result in the incorporation of substantial non-PEG components into the hydrogel composition including crosslinking agents and catalysts, and/or require the use of radiation as a crosslinking initiator. See, for example, U.S. Pat. No. 4,894,238, which describes linear PEG incorporated into a crosslinked network by reaction with a triol and a diisocyanate to form hydrolytically-stable (“nondegradable”) urethane linkages. Another similar approach for preparation of non-degradable PEG hydrogels has been demonstrated by Gayet and Fortier in J. Controlled Release, 38, 177-184 (1996), in which linear PEG was activated as the p-nitrophenylcarbonate and crosslinked by reaction with a protein, bovine serum albumin. Methods such as these result in gels containing non-PEG contaminants. As a result, degradation and dissolution of the matrix can result in undesirable or toxic components being released into the bloodstream. Further, the harsh gelling conditions employed in such methods can often inactivate or degrade drug substances incorporated in such hydrogel compositions.
Early implantable gel delivery systems, as disclosed in U.S. Pat. Nos. 4,938,763 and 5,278,202, were either thermoplastic or thermosetting. The thermoplastic systems involved the formation of polymeric solutions in solvents. Just prior to injection, a curing agent was added to the polymeric solution. After injection, the curing agent caused crosslinking of the polymeric materials and the polymeric solution was exposed to body fluids or water which diffused the solvent away from the polymer-drug mixture, allowing water to diffuse into the mixture. The loss of solvent caused the polymer-drug mixture to coagulate and encapsulate the drug within the polymeric gel. These early gel systems typically used organic solvents to hold the polymer and drug in solution. Organic solvents are often toxic and irritating to tissue.
More recent implantable gel delivery systems have been developed that can be prepared in aqueous solutions. These systems involve a class of block copolymers composed of polyethylene oxide and polypropylene oxide. The polymers are usually synthesized to produce an arrangement of a polypropylene oxide blocks sandwiched between two polyethylene oxide blocks. The polyethylene oxide is hydrophilic while the polypropylene oxide is hydrophobic. The polyethylene oxide and polypropylene oxide copolymers absorb water and form a gel when maintained at a sufficient concentration and heated above a critical temperature. A common polyethylene oxide-polypropylene oxide polymeric solution is known as Poloxamer, a version of which is marketed under the tradename Pluronic™ by the BASF Corporation of Mt. Olive, N.J.
The polyethylene oxide and polypropylene oxide gels are generally less toxic than previous gels that contained or were prepared from organic solvents. However, Poloxamer-based gels are not biodegradable, making drug release from such systems highly unpredictable. Moreover, certain poloxamer based gels have been unsuccessful in clinical trials, due not only to performance limitations, but also due to the adverse side effects attributed to the high concentrations of polymer that must be delivered in order to achieve gelation at body temperature.
In general, the development of hydrogel formulations for drug delivery has progressed rather slowly, partially due to the problems described above and additionally due to problems associated with parenteral administration of hydrogels.
Thus, there is a need for improved polymer and polymer compositions having low toxicity, biodegradability, and favorable release kinetics. Moreover, it would be advantageous if such polymer and polymer compositions could be readily synthesized and characterized, and additionally be used to form gels without the need for additional cross-linking agents, additional co-monomers, and the like. Lastly, it would be highly desirable to provide hydrogel formulations capable of administration by injection, e.g., as free flowing solutions, rather than requiring implantation.
The present invention is based upon the Applicant's preparation of a polymer that meets the above criteria.